PBRM1, SETD2 and BAP1 — the trinity of 3p in clear cell renal cell carcinoma

Biallelic inactivation of the tumour suppressor gene Von Hippel-Lindau (VHL) occurs in the vast majority of clear cell renal cell carcinoma (ccRCC) instances, disrupting cellular oxygen-sensing mechanisms to yield a state of persistent pseudo-hypoxia, defined as a continued hypoxic response despite the presence of adequate oxygen levels. However, loss of VHL alone is often insufficient to drive oncogenesis. Results from genomic studies have shown that co-deletions of VHL with one (or more) of three genes encoding proteins involved in chromatin modification and remodelling, polybromo-1 gene (PBRM1), BRCA1-associated protein 1 (BAP1) and SET domain-containing 2 (SETD2), are common and important co-drivers of tumorigenesis. These genes are all located near VHL on chromosome 3p and are often altered following cytogenetic rearrangements that lead to 3p loss and precede the establishment of ccRCC. These three proteins have multiple roles in the regulation of crucial cancer-related pathways, including protection of genomic stability, antagonism of polycomb group (PcG) complexes to maintain a permissive transcriptional landscape in physiological conditions, and regulation of genes that mediate responses to immune checkpoint inhibitor therapy. An improved understanding of these mechanisms will bring new insights regarding cellular drivers of ccRCC growth and therapy response and, ultimately, will support the development of novel translational therapeutics.